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Kate Harrison, Ismar R Haga, Tali Pechenick Jowers, Seema Jasim, Jean-Christophe Cintrat, Daniel Gillet, Thomas Schmitt-John, Paul Digard, Philippa M Beard
: Poxviruses such as Vaccinia virus (VACV) undertake a complex cytoplasmic replication cycle which involves morphogenesis through four distinct virion forms, and includes a crucial "wrapping" step whereby intracellular mature virions (IMVs) are wrapped in two additional membranes to form intracellular enveloped virions (IEVs). To determine if cellular retrograde transport pathways were required for this wrapping step we examined VACV morphogenesis in cells with reduced expression of the tetrameric tethering factor complex GARP (Golgi-associated retrograde pathway complex), a central component of retrograde transport...
August 31, 2016: Journal of Virology
Shu Yang, Anne G Rosenwald
Macroautophagy/autophagy is a cellular degradation process that sequesters organelles or proteins into a double-membrane structure called the phagophore; this transient compartment matures into an autophagosome, which then fuses with the lysosome or vacuole to allow hydrolysis of the cargo. Factors that control membrane traffic are also essential for each step of autophagy. Here we demonstrate that 2 monomeric GTP-binding proteins in Saccharomyces cerevisiae, Arl1 and Ypt6, which belong to the Arf/Arl/Sar protein family and the Rab family, respectively, and control endosome-trans-Golgi traffic, are also necessary for starvation-induced autophagy under high temperature stress...
October 2, 2016: Autophagy
Brendan R E Ansell, Malcolm J McConville, Louise Baker, Pasi K Korhonen, Samantha J Emery, Staffan G Svärd, Robin B Gasser, Aaron R Jex
Understanding how parasites respond to stress can help to identify essential biological processes. Giardia duodenalis is a parasitic protist that infects the human gastrointestinal tract and causes 200 to 300 million cases of diarrhea annually. Metronidazole, a major antigiardial drug, is thought to cause oxidative damage within the infective trophozoite form. However, treatment efficacy is suboptimal, due partly to metronidazole-resistant infections. To elucidate conserved and stress-specific responses, we calibrated sublethal metronidazole, hydrogen peroxide, and thermal stresses to exert approximately equal pressure on trophozoite growth and compared transcriptional responses after 24 h of exposure...
October 2016: Antimicrobial Agents and Chemotherapy
Judith Manz, Elke Rodríguez, Abdou ElSharawy, Eva-Maria Oesau, Britt-Sabina Petersen, Hansjörg Baurecht, Gabriele Mayr, Susanne Weber, Jürgen Harder, Eva Reischl, Agatha Schwarz, Natalija Novak, Andre Franke, Stephan Weidinger
Gene mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes chromosome 11 open reading frame 30 (C11orf30) and leucine rich repeat containing 32 (LRRC32). Using a targeted resequencing approach we identified low-frequency and rare missense mutations within the LRRC32 gene encoding the glycoprotein A repetitions predominantly (GARP), a receptor on activated regulatory T cells that binds latent TGFβ...
July 20, 2016: Journal of Investigative Dermatology
David C Gershlick, Christina Schindler, Yu Chen, Juan S Bonifacino
Endosomes function as a hub for multiple protein-sorting events, including retrograde transport to the trans-Golgi network (TGN) and recycling to the plasma membrane. These processes are mediated by tubular-vesicular carriers that bud from early endosomes and fuse with a corresponding acceptor compartment. Two tethering complexes named GARP (composed of ANG2, VPS52, VPS53, and VPS54 subunits) and EARP (composed of ANG2, VPS52, VPS53, and Syndetin subunits) were previously shown to participate in SNARE-dependent fusion of endosome-derived carriers with the TGN and recycling endosomes, respectively...
September 15, 2016: Molecular Biology of the Cell
Hui-Ting Chou, Danijela Dukovski, Melissa G Chambers, Karin M Reinisch, Thomas Walz
We show here that the Saccharomyces cerevisiae GARP complex and the Cog1-4 subcomplex of the COG complex, both members of the complexes associated with tethering containing helical rods (CATCHR) family of multisubunit tethering complexes, share the same subunit organization. We also show that HOPS, a tethering complex acting in the endolysosomal pathway, shares a similar architecture, thus suggesting that multisubunit tethering complexes use related structural frameworks.
August 2016: Nature Structural & Molecular Biology
Moira Paroni, Andrea Magarotto, Silvia Tartari, Giulia Nizzoli, Paola Larghi, Giulia Ercoli, Umberto Gianelli, Massimiliano Pagani, Luca Elli, Sergio Abrignani, Dario Conte, Jens Geginat, Flavio Caprioli
OBJECTIVES: To provide a functional and phenotypic characterization of immune cells infiltrating small intestinal mucosa during non-IPEX autoimmune enteropathy (AIE), as to gain insights on the pathogenesis of this clinical condition. METHODS: Duodenal biopsies from a patient with AIE at baseline and following drug-induced remission were analyzed by immunohistochemistry, immunofluorescence, and flow cytometry, and results were compared with those obtained from patients with active celiac disease, ileal Crohn's disease and healthy controls...
2016: Clinical and Translational Gastroenterology
Kai Li, Fuchao Chen, Huijuan Xie
Neoadjuvant chemotherapy (NACT) has been an increasingly used therapeutic strategy to improve the outcome of advanced gastric cancer (GC) over the past few decades. Lymphocytic infiltration has been reported to be associated with response to NACT, but the immune cell subpopulation and its prognosis contributing to response in GC have not been clarified yet. In the current study, the tumor infiltration of FOXP3+ and GARP+ regulatory T-cells (Tregs, marked by FOXP3 and GARP) response to NACT in advanced GC and their correlation with prognosis were evaluated...
2016: OncoTargets and Therapy
Alassane S Barro, Mark Fegan, Barbara Moloney, Kelly Porter, Janine Muller, Simone Warner, Jason K Blackburn
The ecology and distribution of B. anthracis in Australia is not well understood, despite the continued occurrence of anthrax outbreaks in the eastern states of the country. Efforts to estimate the spatial extent of the risk of disease have been limited to a qualitative definition of an anthrax belt extending from southeast Queensland through the centre of New South Wales and into northern Victoria. This definition of the anthrax belt does not consider the role of environmental conditions in the distribution of B...
June 2016: PLoS Neglected Tropical Diseases
Susanne A Hahn, Annemarie Neuhoff, Jenny Landsberg, Jonathan Schupp, Daniela Eberts, Petra Leukel, Matthias Bros, Martin Weilbaecher, Detlef Schuppan, Stephan Grabbe, Thomas Tueting, Volker Lennerz, Clemens Sommer, Helmut Jonuleit, Andrea Tuettenberg
In melanoma patients, one of the main reasons for tumor immune escape and therapy failure is the immunosuppressive tumor microenvironment. Herein, suppressive immune cells and inhibitory factors secreted by the tumor itself play a central role.In the present study we show that the Treg activation marker GARP (glycoprotein A repetitions predominant), known to induce peripheral tolerance in a TGF-β dependent way, is also expressed on human primary melanoma. Interestingly, membrane bound GARP is shed from the surface of both, activated Treg and melanoma cells, and, in its soluble form (sGARP), not only induces peripheral Treg but also a tumor associated (M2) macrophage phenotype...
May 27, 2016: Oncotarget
Sudhanshu Agrawal, Sreerupa Ganguly, Alexander Tran, Padmaja Sundaram, Anshu Agrawal
Aged subjects display increased susceptibility to mucosal diseases. Retinoic Acid (RA) plays a major role in inducing tolerance in the mucosa. RA acts on Dendritic cells (DCs) to induce mucosal tolerance. Here we compared the response of DCs from aged and young individuals to RA with a view to understand the role of DCs in age-associated increased susceptibility to mucosal diseases. Our investigations revealed that compared to young DCs, RA stimulated DCs from aged subjects are defective in inducing IL-10 and T regulatory cells...
June 2016: Aging
Anne Spang
Vesicles that are generated by endocytic events at the plasma membrane are destined to early endosomes. A prerequisite for proper fusion is the tethering of two membrane entities. Tethering of vesicles to early endosomes is mediated by the class C core vacuole/endosome tethering (CORVET) complex, while fusion of late endosomes with lysosomes depends on the homotypic fusion and vacuole protein sorting (HOPS) complex. Recycling through the trans-Golgi network (TGN) and to the plasma membrane is facilitated by the Golgi associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes, respectively...
2016: Frontiers in Cell and Developmental Biology
Stéphanie Liénart, Julie Stockis, Olivier Dedobbeleer, Sophie Lucas
Reducing Treg function in cancer patients should augment antitumor immune responses. We recently uncovered a mechanism of immunosuppression by human Tregs that implies transmembrane protein GARP and production of active TGF-ß1. We obtained monoclonal antibodies that block this process and could thus serve as a novel approach for cancer immunotherapy.
March 2016: Oncoimmunology
Marjolein J Peters, Yolande F M Ramos, Wouter den Hollander, Dieuwke Schiphof, Albert Hofman, André G Uitterlinden, Edwin H G Oei, P Eline Slagboom, Margreet Kloppenburg, Johan L Bloem, Sita M A Bierma-Zeinstra, Ingrid Meulenbelt, Joyce B J van Meurs
OBJECTIVE: To identify molecular biomarkers for early knee osteoarthritis (OA), we examined whether joint effusion in the knee associated with different gene expression levels in the circulation. MATERIALS AND METHODS: Joint effusion grades measured with magnetic resonance (MR) imaging and gene expression levels in blood were determined in women of the Rotterdam Study (N=135) and GARP (N=98). Associations were examined using linear regression analyses, adjusted for age, fasting status, RNA quality, technical batch effects, blood cell counts, and BMI...
2016: F1000Research
Liping Sun, Hao Jin, Hui Li
There are many molecules that define regulatory T cells (Tregs) phenotypically and functionally. Glycoprotein A repetitions predominant (GARP) is a transmembrane protein containing leucine rich repeats. Recently, GARP is found to express highly on the surface of activated Tregs. The combination of GARP and other surface molecules isolates Tregs with higher purity. Besides, GARP is a cell surface molecule of Tregs that maintains their regulatory function and homeosatsis. GARP has also been proved to promote the activation and secretion of transforming growth factor β (TGF-β)...
April 15, 2016: Oncotarget
Ephraim A Ansa-Addo, Jessica Thaxton, Feng Hong, Bill X Wu, Yongliang Zhang, Caroline W Fugle, Alessandra Metelli, Brian Riesenberg, Katelyn Williams, Daniel T Gewirth, Gabriela Chiosis, Bei Liu, Zihai Li
As an endoplasmic reticulum heat shock protein (HSP) 90 paralogue, glycoprotein (gp) 96 possesses immunological properties by chaperoning antigenic peptides for activation of T cells. Genetic studies in the last decade have unveiled that gp96 is also an essential master chaperone for multiple receptors and secreting proteins including Toll-like receptors (TLRs), integrins, the Wnt coreceptor, Low Density Lipoprotein Receptor-Related Protein 6 (LRP6), the latent TGFβ docking receptor, Glycoprotein A Repetitions Predominant (GARP), Glycoprotein (GP) Ib and insulin-like growth factors (IGF)...
2016: Current Topics in Medicinal Chemistry
Justin P Edwards, Timothy W Hand, Denise Morais da Fonseca, Deborah D Glass, Yasmine Belkaid, Ethan M Shevach
Treg cells can secrete latent TGF-β1 (LTGF-β1), but can also utilize an alternative pathway for transport and expression of LTGF-β1 on the cell surface in which LTGF-β1 is coupled to a distinct LTGF-β binding protein termed glycoprotein A repetitions predominant (GARP)/LRRC32. The function of the GARP/LTGF-β1 complex has remained elusive. Here, we examine in vivo the roles of GARP and TGF-β1 in the induction of oral tolerance. When Foxp3(-) OT-II T cells were transferred to wild-type recipient mice followed by OVA feeding, the conversion of Foxp3(-) to Foxp3(+) OT-II cells was dependent on recipient Treg cells...
June 2016: European Journal of Immunology
Sven Fridrich, Susanne A Hahn, Marion Linzmaier, Matthias Felten, Jenny Zwarg, Volker Lennerz, Andrea Tuettenberg, Walter Stöcker
GARP (glycoprotein A repetitions predominant) is a cell surface receptor on regulatory T-lymphocytes, platelets, hepatic stellate cells and certain cancer cells. Its described function is the binding and accommodation of latent TGFβ (transforming growth factor), before the activation and release of the mature cytokine. For regulatory T cells it was shown that a knockdown of GARP or a treatment with blocking antibodies dramatically decreases their immune suppressive capacity. This confirms a fundamental role of GARP in the basic function of regulatory T cells...
2016: PloS One
Yukari Nagatoshi, Nobutaka Mitsuda, Maki Hayashi, Shin-Ichiro Inoue, Eiji Okuma, Akihiro Kubo, Yoshiyuki Murata, Mitsunori Seo, Hikaru Saji, Toshinori Kinoshita, Masaru Ohme-Takagi
Stomatal movements regulate gas exchange, thus directly affecting the efficiency of photosynthesis and the sensitivity of plants to air pollutants such as ozone. The GARP family transcription factors GOLDEN 2-LIKE1 (GLK1) and GLK2 have known functions in chloroplast development. Here, we show that Arabidopsis thaliana (A. thaliana) plants expressing the chimeric repressors for GLK1 and -2 (GLK1/2-SRDX) exhibited a closed-stomata phenotype and strong tolerance to ozone. By contrast, plants that overexpress GLK1/2 exhibited an open-stomata phenotype and higher sensitivity to ozone...
April 12, 2016: Proceedings of the National Academy of Sciences of the United States of America
H Meyer-Martin, S A Hahn, H Beckert, C Belz, A Heinz, H Jonuleit, C Becker, C Taube, S Korn, R Buhl, S Reuter, A Tuettenberg
BACKGROUND: Regulatory T cells (Treg) represent a promising target for novel treatment strategies in patients with inflammatory/allergic diseases. A soluble derivate of the Treg surface molecule glycoprotein A repetitions predominant (sGARP) has strong anti-inflammatory and regulatory effects on human cells in vitro as well as in vivo through de novo induction of peripheral Treg. The aim of this study was to investigate the immunomodulatory function of sGARP and its possible role as a new therapeutic option in allergic diseases using a humanized mouse model...
September 2016: Allergy
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